Abstract 11552: CTCF is Indispensable for the Gene Expression of Estrogen Receptors in the Arterial Smooth Muscle Cell: Defensive Mechanism Against Atherosclerosis
Purpose Estrogen modulates atherosclerosis through estrogen receptors (ER α and β) on the arterial smooth muscle cell (SMC). Hemodynamic stress on the arterial wall will produce deformation of nuclear matrix in the SMC. We hypothesize that CCCTC-binding factor (CTCF) tightly associating with nuclear matrix transmits the mechanical stress and regulates epigenetic control of the transcription of ER gene. The purpose of this study is to evaluate the role of CTCF on the ER gene expression in coronary arterial SMC.
Methods and Results In cultured human coronary arterial SMC down regulation of CTCF expression by knockdown of CTCF mRNA (29%) using specific siRNA significantly suppressed the gene expression of ER-α to 28 ± 5% and ER-β to 36 ± 4% (each; p<0.01, n=6) by quantitative real-time PCR. Over expression of CTCF by transfection with cDNAs encoding full-length human CTCF did not significantly influence the extent of ER-α and -β expression. SMC stretched periodically on the silicone membrane for 4 hours the expression of ER-α was reduced to 45 ± 3% and ER-β to 61 ± 9%. (each; p<0.01, n=6). These reductions were completely cancelled by over expression of CTCF through transfection with CTCF cDNA. Immunohistochemistry of the normal coronary arteries of human autopsy samples demonstrated the immunoreactivities (IR) of CTCF, ER-α and ER-β in most part of the medial SMC nuclei. But, the regions of the shoulder and fibrous cap of the stable atherosclerotic plaque in the neointima the IR of CTCF patchily disappeared, which was accompanied by disappearance of IR of ERs. Moreover, The IR of both CTCF and ERs completely disappeared in the fibrous cap of the ruptured plaque of the patients with acute myocardial infarction.
Conclusion CTCF supports the expression of ERs in the arterial SMC and works protectively against the mechanical stress in the process of atherosclerosis.
- © 2012 by American Heart Association, Inc.